The prognosis of patients with metastatic uveal melanoma (“UM”) is poor with a median 1-year survival rate of less than 30% [1] [2]. In 87% of patients, metastasis will develop primarily in the liver, and there are limited therapeutic options for this disease [3] [4]. Activating mutations in G-protein alpha subunits GNAQ or GNA11 are early oncogenic events in UM development [5] and result in the activation of the MAPK pathway [6]. We have reported that the small molecule MEK inhibitor selumetinib can inhibit pERK and cyclin D1, resulting in decreased viability of UM cell lines [7]. Furthermore, in patients with UM, selumetinib can result in tumor shrinkage, and the sustained inhibition of pERK may be predictive of benefit [8].
MEK inhibitors have been reported to give a partial or stable response in tumors with activated MAPK pathway, including melanoma and solid malignancies [9], [10] [11]. However, the use of small molecule MEK inhibitors has been undermined by acquired drug resistance [12], which reduces the efficacy of these drugs in the clinical setting (patients resistant to the drug being “non-responders”). For example, resistance to selumetinib has been described in colorectal cancer cells carrying BRAF and RAS mutations, where resistance is mediated by the amplification of the driving oncogene [13] [14]. In cutaneus melanoma, MEK1 mutations have been found to confer resistance to MEK inhibitors [15]. In uveal melanoma with GNAQ mutations, the mechanisms of acquired resistance have been elusive and more effective therapies are needed for the treatment of this disease.
The RNA helicase DDX43 was first identified as a cancer/testis antigen, and it is highly expressed in many tumor types compared to normal tissues [16, 52], including melanoma [19]. In particular, DDX43 was found to be overexpressed in 50% acute myeloid leukemias (CML) [17], and its expression is associated with advanced disease and poor prognosis [18]. It has been reported that DDX43 promoted expression of RAS protein through RNA unwinding [20].
DDX43, also called HAGE, is a member of the DEAD-box family of ATP-dependent RNA helicases. These proteins browse RNA molecules and promote the dissociation of the RNA from ribonucleoproteins to which they have high affinity [21]. In this way RNA helicases support processes like transcription, pre-mRNA splicing, translation initiation/elongation, and RNA degradation [22] [23]. Their altered expression levels have been also implicated in tumor initiation, progression and maintenance [24].